Comprehensive Histologic Assessment Helps to Differentiate Multiple Lung Primary Nonsmall Cell Carcinomas From Metastases

Abstract

The pathological classification of non-small cell lung cancer (NSCLC) is evolving. Lung adenocarcinoma is morphologically heterogeneous, with mixtures of acinar, papillary, bronchioloalveolar and solid patterns in more than 80% of cases. In case of synchronous or metachronous multiple NSCLC, the distinction of intrapulmonary metastases from independent primary tumors is of great clinical importance since it influences staging and potentially the therapeutic strategy. Here we took advantage of a cohort of 20 patients with 42 multiple NSCLC tumors (24 potential pair comparisons) that were annotated molecularly using genomic and mutational profiling to evaluate the value of comprehensive histologic assessment in this setting. Using the Martini-Melamed criteria, paired tumors were characterized as multiple primary NSCLCs in 21 cases and as intra-pulmonary metastases in 3 cases. Genomic and mutational data led to a diagnosis of multiple primaries in 14 cases and of metastases in 8 cases; 2 cases could not be assessed. This molecular characterization contradicted the Martini-Melamed diagnosis in 7 (32%) of the 22 assessable comparisons. Adenocarcinoma was found in 32 (76%) of the 42 tumors. After review in a blinded fashion, semiquantitative comprehensive histologic assessement of paired tumors was different in 16 and similar in 8 paired tumors. We found that comparing adenocarcinomas is a complex issue that requires assessment not only of percentages of the histologic subtypes, but also the recording of additional histologic details such as cytologic features, patterns of stroma, necrosis, discrete nodularity versus miliary growth and variants such as clear cell, signet ring, mucinous, and fetal patterns. We also found that paired squamous cell carcinomas could be compared based on histologic subtyping in addition to cytologic and stromal characteristics. Considering histologically different tumors as multiple primaries, and similar tumors as metastases, comprehensive histologic subtyping was consistent with the molecular characterization in 20 (91%) of the 22 pairs comparisons. In summary, based on a well characterized cohort with detailed clinical, pathologic and molecular data, we found comprehensive histologic assessment is a powerful tool that appears to be a promising way to determine whether multiple lung adenocarcinomas or squamous cell carcinomas are metastatic or multiple primaries. This has great clinical implications for staging and therapeutic management of lung cancer patients with multiple tumors. Given its high correlation with molecular characterization of such tumors, it may provide a much cheaper and faster method to address this problem

Morphological and molecular approach to synchronous non-small cell lung carcinomas: impact on staging

“…Similar to previously published studies, in our study histo-molecular characterization correlated with Martini-Melamed criteria in about 50% of the cases, including both adenocarcinoma and squamous cell carcinoma. 4,5,9,16,17 This is not surprising as morphological subtying of lung adenocarcinoma has changed in the past decade, and the proposed detailed approach has been implemented in the 2015 World Health Organization classification of lung tumors. 18 Adenocarcinoma of the lung is morphologically heterogenous and careful comparison of morphological subtypes between two tumors is potentially useful in staging of synchronous tumors.…”

Assessment of invasion in lung adenocarcinoma classification, including adenocarcinoma in situ and minimally invasive adenocarcinoma

“…It may also be helpful in staging evaluation of multiple nodules to compare histological patterns of adenocarcinoma within different tumor nodules. 33 In addition, the future holds expansion of insights into molecular pathogenesis that may have morphological associations.…”

Two Lung Adenocarcinomas in the Same Lobe: Multiple Primaries or Intrapulmonary Metastasis?

“…4) Girard et al concluded comprehensive histologic assessment methodology is a powerful tool in determining whether multiple adenocarcinomas or squamous cell carcinomas are metastatic or multiple primaries. 5) In their series, however, the diagnoses based on the methodology were inconsistent with molecular characterization results in 2 (9%) of the 22 comparison pairs. Based on their methodology, our case is diagnosed as double primaries, but both tumors had the same EGFR mutation.…”